Removal of the N-propeptide of procollagen II and I is required for proper fibril assembly. Mutations in procollagen I/II N-propeptidase, a member of the ADAMTS family (ADAMTS-2) cause a recessively inherited skin disorder, Ehlers-Danlos syndrome VIIC (dermatosparactic type) in humans and dermatosparaxis in a variety of animals. The molecular hallmark of this disorder is the presence of abnormal fibrils containing Collagen with an intact N-propeptide. Intriguingly, while procollagen I is a major component of bone, ligament, sclera and aorta, these tissues are relatively normal. The presence of fully processed Collagen I in these tissues and skin, as well as normal procollagen II processing in dermatosparactic cartilage suggests the presence of other N-propeptidases. ADAMTS-2, ADAMTS-3 and ADAMTS-14 comprise the total genomic complement of the procollagen N-propepticlase (PCNP) group of the ADAMTS family. ADAMTS-14 processes procollagen 1, albeit inefficiently. We recently discovered that ADAMTS-3 processes the N-propeptide of procollagen II and is the major PCNP expressed in cartilage. The hypothesis of this study is that ADAMTS-3 is the major procollagen II N-propeptidase and may contribute to procollagen I processing in some tissues. We will investigate the precise biological role(s) of ADAMTS-3 by generation and analysis of transgenic mice with inactivated Adamts3 alleles. The significance of the proposed studies is that they offer insights on the fundamental biology of procollagen processing and dermatosparaxis and may uncover novel biological roles for ADAMTS-3. In the long-term, this information may be useful for treatment of dermatosparaxis.